Battle of the Bands: Can You Deny the PPI?

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1 Battle of the Bands: Can You Deny the PPI? Andrea Whitaker, PharmD. PGY1 Pharmacy Practice Resident University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center University of Texas Health Science Center at San Antonio January 6, 2017 Learning Objectives 1. Describe cirrhosis pathophysiology and esophageal varices development 2. Explain treatment options available for esophageal varices 3. Review current treatment evidence for proton pump inhibitors (PPI) in esophageal varices after endoscopic variceal band ligation (banding) 4. Identify treatment recommendation for PPIs in patients with esophageal varices postbanding based on available literature

2 Battle of the Bands: Can You Deny the PPI Andrea Whitaker, PharmD. PGY1 Pharmacy Practice Resident University Health System, San Antonio, TX Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center University of Texas Health Science Center at San Antonio January 6, 2017 Learning Objectives: At the completion of this activity, the participant will be able to: 1. Describe cirrhosis pathophysiology and esophageal varices development 2. Explain treatment options available for esophageal varices 3. Review current treatment evidence for proton pump inhibitors (PPI) in esophageal varices after endoscopic variceal band ligation (banding) 4. Identify treatment recommendation for PPIs in patients with esophageal varices based on available literature Assessment Questions: 1. T F Varices are a complication of cirrhosis that develop as a mechanism to overcome the portal hypertension 2. What are the safety concerns associated with using PPI in cirrhotic patients? A. Risk for pneumonia in 30 days B. Risk for SBP within 90 days C. Risk for Clostridium difficile infection in 90 days D. All of the above 3. T F If a PPI is going to be used post-banding the maximum duration should be 10 days. ***To obtain CE credit for attending this program please sign in. Attendees will be ed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com *** Faculty (Speaker) Disclosure: Andrea Whitaker has indicated she has no relevant financial relationships to disclose relative to the content of her presentation. A. Whitaker 2 of 20

3 GASTROINTESTINAL BLEEDS I. Upper and Lower Gastrointestinal (GI) Bleeds A. Lower 1 B. Upper 1 1. Bleeding originating from distal portion of duodenum (ligament of Treitz) to rectum 2. Classifications a. Vascular b. Inflammatory c. Tumors d. Traumatic e. Iatrogenic 1. Bleeding from esophagus to ligament of Treitz 2. Classifications a. Non-variceal (1) Ulcerative (2) Vascular (3) Traumatic (4) Iatrogenic (5) Tumors b. Variceal/portal hypertension CIRRHOSIS I. Definition A. Irreversible liver fibrosis due to chronic inflammation and damage 2 B. End-stage chronic liver disease diagnosis 3,4 II. Etiology 3-5 A. Developed countries 1. Hepatitis C 2. Alcohol abuse 3. Non-alcoholic liver disease B. Underdeveloped countries 1. Hepatitis B C. Prevalence is underreported due to early stages being asymptomatic III. Epidemiology A. United States prevalence: 0.27% equating to ~ 600,000 adults 4,5 B. 8 th leading cause of death in United States 2 A. Whitaker 3 of 20

4 IV. Classifications A. Compensated cirrhosis 4 1. Asymptomatic a. ± gastroesophageal varices b. No cirrhosis complications 2. Child-Pugh score A See Appendix A 3. Life expectancy: years 2 B. Decompensated cirrhosis 4 V. Cirrhosis Complications Symptomatic cirrhosis a. Cirrhotic complications develop 2. Child-Pugh score B or C - See Appendix A 3. Life expectancy: 2 years 2 A. Portal hypertension 1. First cirrhosis consequence 2. Underlying cause for all other complications B. Hepatic encephalopathy C. Ascites D. Spontaneous bacterial peritonitis (SBP) E. Hepatorenal syndrome F. Varices and variceal bleed/hemorrhage VARICES AND VARICEAL BLEEDS I. Epidemiology A. Approximately 50% of cirrhotic patients have varices and development correlates with disease severity 4 1. Child-Pugh A ~ 40% have varices 2. Child-Pugh C ~ 85% have varices B. Risk of developing varices is 7-8% each year 3,4 C. Risk of bleeding from varices is 12% each year 3.4 II. Pathophysiology 4 A. Portal hypertension Chronic inflammation Resistance of portal blood flow Blood pools in portal vein Increasee pressure in portal vein Chronic portal hypertension Figure 1: Portal Hypertension Development A. Whitaker 4 of 20

5 1. Compensatory mechanism to overcome portal hypertension a. Increase in nitric oxide vasodilation of intrahepatic blood flow b. Increase in splanchnic vasculature vasoconstriction decrease blood flow to portal vein Figure 2: Portal Venous System Figure 3: Esophageal Varices B. Variceal formatio 6,7 1. Compensatory mechanism insufficient to overcome increased portal pressure 2. New or reopening embryotic vasculature allowing blood to by bass liver a. Structurally, variceal vasculature is fragile and has low elasticity C. Variceal rupture 4,6,7 Increased portal pressure Increased variceal wall tension Variceal enlargement Decreased stability of vessels Vessel rupture Figure 4: Variceal Rupture Development 1. Predictors for variceal bleed a. Hepatic venous pressure gradient (HVPG): > 12 mmhg 4,6,7 (1) Difference in pressure between portal vein and intraabdominal vena cava pressure 8 (2) Appendix B describes HVPG interpretations A. Whitaker 5 of 20

6 III. Diagnosis A. Portal hypertension b. Endoscopic findings: red signs and variceal size of medium or large 4,6,7 (1) Red wale sign: longitudinal veins on varices surface that looks like a whip mark and often red in color (2) Refer to Appendix C for details about variceal size c. Decompensated cirrhosis: Child-Pugh score B or C 4,6,7 1. HVPG > 5 mmhg Appendix B 4 B. Varices IV. Treatment Overview 4 1. Gold Standard esophagogastroduodenoscopy (EGD) 4 A. Primary prophylaxis 4 a. Classified by size Appendix C b. EGD done at cirrhosis diagnosis to screen for varices Table 1: Primary prophylaxis treatment for variceal bleeds Variceal Classification Treatment EGD Screening No Varices none CC: every 2-3 years Small varices without risk factors ± non-selective β blocker CC: every 1-2 years, if no β-blocker DC: yearly Small varices non-selective with risk factors β blocker None Medium/large varices non-selective without risk factors β-blocker None Medium/large varices non-selective with risk factors 1 β-blocker or banding None Factors: Child-Pugh B/C, red wale marks or spots on EGD; CC: compensated cirrhosis; DC: decompensated cirrhosis; 1Risk banding: endoscopic variceal band ligation B. Acute variceal bleeding (AVB) 1. Hemodynamic stability 3,4,9 a. Blood volume resuscitation (1) Goal hemoglobin: ~ 7-8 g/dl (2) Higher goals increase re-bleeding and mortality b. Use normal saline cautiously (1) Increase risk for ascites and fluid accumulation c. Fresh frozen plasma and platelets (1) For coagulopathies or thrombocytopenia present 2. SBP prophylaxis a. Increased SBP risk during variceal bleeding 4,10 (1) Invasive procedures increase bacteremia risk A. Whitaker 6 of 20

7 (2) Infection causes inflammatory cascade and release of vasoactive peptides increasing variceal pressure (a) Increased risk for rupture and re-bleeding (3) Decompensated cirrhosis > compensated cirrhosis b. Decreased rates of SBP and mortality 4,11 c. Treatment: ceftriaxone 1 g IV daily for 5-7 days 4 (1) Alternative: ciprofloxacin 400 mg IV twice daily 3. Management of bleeding a. Pharmacologic therapy + EGD therapy 4 (1) EGD therapy plus pharmacologic therapy shown to be most efficacious 4,12 Table 2: Meta-analysis on efficacy of combination therapy 12 EGD therapy + EGD therapy pharmacologic therapy* alone Initial hemostasis ** 88% 76% Control of bleeding at day 5 5 day mortality 7% 9% Relative Risk (95% confidence interval) 1.10 ( ) 77% 58% 1.28 ( ) 0.73 ( ) *Pharmacologic therapy varied between trials - octreotide, somatostatin, vapreotide, or terlipressin for 2-5 days **Hemostasis defined as the clinical absence of continued bleeding within 6 to 48 hours of treatment; b. Pharmacologic therapy (1) Somatostatin analogues 4,13 Table 3: Drug information on octreotide Drug Mechanism of action Dose Side Effects Clinical Pearls Octreotide Selective splanchnic 50 µg IV bolus, Sinus bradycardia Tachyphlaxis vasoconstriction via direct then 50 µg/ Hyper/o-glycemia vasoconstriction and hours studied Abdominal pain inhibition of glucagon, up to 5 days serotonin, gastrin, VIP, and Fatigue insulin Headache (2) Alternative Treatments 4,13 (a) Vasopressin ± nitroglycerin 1. Potent splanchnic vasoconstrictor 2. Use limited by adverse effects of peripheral ischemia, arrhythmias, hypertension, and bowel ischemia 3. Maximum duration for 24 hours due to side effect development A. Whitaker 7 of 20

8 C. Secondary prophylaxis for variceal bleed 4 1. Combination therapy of non-selective β -blocker and banding 2. Repeat banding every 7-14 days until varices have eradicated 3. Repeat EGD every 3-6 months to evaluate for variceal recurrence ENDOSCOPIC THERAPY Table 4: Comparison of EGD therapies for variceal treatment EGD therapy Sclerotherapy 14 Banding Technique Duration Benefits Injection of sclerosant causing thrombosis in vessel and inflammation in surrounding tissue ~5 sessions every 14 days until eradicated Cheap Easy to perform Complications Esophageal ulcers Bleeding ulcers Fever Retrosternal chest pain Dysphagia Esophageal strictures Bacteremia and infections portal pressure Pearls Complications are unpredictable Experience by endoscopist can affect the outcome EGD places rubber bands around bleeding varices ~4 sessions every 14 days until eradicated Fewer complications Shallow ulcers Bleeding ulcer Transient dysphagia, chest discomfort Esophageal laceration and perforation Retrosternal chest pain Esophageal strictures I. Banding is preferred treatment 14 A. Ulcers developed are more shallow compared to sclerotherapy 1. Average post-banding ulcer size (± standard deviation): 10.4 ± 5.1 mm 17 B. Greater initial control of bleeding and reduced re-bleeding Risk factors for re-bleeding 16,18,19 a. Emergent banding b. Child-Pugh score 9 c. MELD 18 d. Alcoholic cirrhosis C. Re-bleeding risk after banding 1-3% compared to 20% with sclerotherapy 16,18,19 II. PPI have been used to reduce gastric ulcers and re-bleeding A. Increased 6% mortality for every 1 mm increase in gastric or duodenal ulcer >10 mm 21 B. Inconsistent results on whether they provide benefit and/or prevent re-bleeding post banding 16,18,19 A. Whitaker 8 of 20

9 CLINICAL CONTROVERSY I. Are PPIs harmful in cirrhotic patients after endoscopic therapy for varices? II. How effective are PPIs in preventing re-bleeding after banding? III. How long should PPIs be used after banding? IV. What dose of PPI should be used? PROTON PUMP INHIBITORS I. Mechanism of action A. Inhibits the parietal cell H + /K + ATP pump decreasing HCl secretion 13,22-23 B. Increases the gastric ph to II. Adverse effects13,22 1. Improves clot formation, platelet aggregation and decreases fibrinoloysis A. Minimal short term adverse effects 1. Headache, nausea, vomiting, abdominal pain III. Warnings and precautions Table 5: Warning and precautions for PPI in general population Warning and Precautions Hypothesized mechanism Duration of PPI use Pneumonia 27 Decreased acidic environment alters leukocyte function Development of colonization in the upper gastrointestinal tract Within first 30 days Clostridium difficile infection (CDI) 28 Decreased acidic environment promotes germination of spores Altered leukocyte and other immunological functions with ph changes Altered toxin production by organism 90 days to 2 years Hypomagnesemia 13,22 Unspecified 3 months Vitamin B12 deficiency 13,22 Decreased acidity, decreases absorption 1-2 years Osteoporosis related bone Decrease calcium absorption leading to fractures 29 decreased bone density 1-4 year Inhibits osteoclast activity A. Whitaker 9 of 20

10 IV. Current Place in Therapy A. Non-variceal ulcers/bleeding 1. Active gastric or duodenal ulcer bleed 25 a. PPI used after EGD therapy stops bleeding (1) Shown to reduce re-bleeding and surgery b. Dose: pantoprazole or omeprazole 80 mg IV bolus followed by continue infusion of 8 mg/hour for 72 hours, then 40 mg by mouth daily thereafter 2. Gastric or duodenal ulcer healing a. Pantoprazole or omeprazole 40 mg once daily for 2-8 weeks or indefinitely depending on precipitating cause Other conditions 13,22 a. GERD b. Erosive esophagitis c. Hypersecretory conditions EVALUATION OF PPI USE IN CIRRHOSIS I. Prescribing Habits II. Safety A. PPI use without indication in cirrhotic patients: % Risk factors associated with inappropriate use 32 a. Esophageal varices (1) Continued use for 2-6 months observed b. Prescribed PPI during hospital stay A. Increased risk for SBP associated with PPI use 31,35 1. PPIs decrease acidic environment lowering defense mechanism against bacteria and increased bacterial overgrowth a. Increases risk for SBP by 4.3 times 3 b. Increased risk observed within 90 days 31,34,36 2. SBP increases risk for mortality 37 a. In-hospital mortality with first event: 10-50% b. 1-year mortality after first event: 31-93% B. Development of CDI increases in-hospital mortality and length of stay in cirrhotic patients compared to non-cirrhotic patients 38 III. Efficacy A. Esophageal Varices 16,18,19 1. Inconsistent results on use of PPI providing protection from re-bleeding after banding A. Whitaker 10 of 20

11 Table 6: Guideline Recommendations Source Year Recommendations AASLD Guidelines Studies favor use post-banding Lo and colleagues Systematic review Post-banding: 10 days of therapy is reasonable Acute variceal bleed: should be stopped as soon as variceal bleed is the cause UK Guidelines on variceal hemorrhage No, unless peptic ulcer disease Table 7: Univariate analysis of PPI for reducing risk of re-bleeding post-banding Study Design n p-value Sinclair et al Retrospective cohort 728 NS Vanbievliet et al Case-control 101 NS Kang et al Retrospective cohort LITERATURE REVIEW Alaniz C, Mohammad RA, Welage LS. Pharmacotherapy. 2009;29(3): Objective Evaluate the use of PPI in acute variceal hemorrhage Design/Method Single center, retrospective cohort study Patient Population Variceal hemorrhage diagnosed by EGD Intervention Treatment group (PPI group) Octreotide + pantoprazole >24 hours Control group: Octreotide alone Octreotide + pantoprazole <24 hours Octreotide + intermittent acid suppression Endpoints Primary Endpoint Units of packed red blood (PRBC) cells transfused during hospitalization Baseline Characteristics Secondary Endpoints Number of FFP, platelets, and cryoprecipitate transfused Endoscopic intervention Re-bleeding Mortality rate Average age was 52 and majority of participants were male Control (n=77) PPI (n=53) p-value Child Pugh Score, n ±SD 9.4 ± ±2.4 NS Prior variceal bleed, n (%) 44 (57) 23 (43) NS β-blocker at entry, n (%) 35 (45) 16 (30) NS Hemoglobin level (g/dl) 9.1 ± ± 2.2 NS Duration of infusion (hours) Octreotide 48.4 ± ± Pantoprazole 3.5 ± ± 48.9 <0.001 A. Whitaker 11 of 20

12 Results Control (n=77) PPI (n=53) p-value PRB transfused throughout hospitalization, mean ± SD 5.8 ± ± 6.5 NS FFP transfused throughout hospitalization, mean ± SD 2.9 ± ± Recurrent variceal bleed 1, n (%) 4 (5) 7 (13) NS Mortality, n (%) 13 (17) 7 (13) NS Endoscopic intervention, n (%) Banding 31 (40) 22 (42) NS Sclerotherapy 23 (30) 19 (36) NS TIPS 24 (31) 18 (34) NS Authors Conclusion No benefit in prolonged continuous infusion (>24 hours) of pantoprazole compared to short term (<24 hours) Strengths Only study to evaluate immediate use of a PPI in variceal bleeds Methods allow for high external validity Limitation/Critique Retrospective study o Did not specific the duration of follow up for endpoints which are important for re-bleeding and mortality o Time to EGD therapy not reported; within 12 hours is standard of care Questionable severity of patients o Initial Hgb > 8 g/dl which is above goal transfusion o Control might have lower severity of patients compared to PPI group based on octreotide o ICU LOS was not reported even though it was a stated endpoint Now powered for detecting re-bleeding Primary endpoint inappropriate for determining PPI benefit as its place in therapy reduced re-bleeding Take away In the first 24 hours there is no harm and no benefit in using PPI for acute variceal bleed 1Determined by use of blood transfusion after initial stabilization, repeated endoscopy, or repeated transjugular intrahepatic portosystemic shunting; NS: Not statistically significant; SE: standard error; FFP: fresh frozen plasma; ICU: intensive care unit; LOS: length of stay A. Whitaker 12 of 20

13 Shaheen NJ, Stuart E, Schmitz SM, et al. Pantoprazole reduces the size of post-banding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005; 41: Objective Evaluate the use of proton pump inhibitors with elective variceal band ligation Design/Method Randomized, double-blind, placebo-controlled Patient Population Inclusion: Portal hypertension with varices History of variceal hemorrhage Having elective banding Exclusion: Pre-existing esophageal ulcers Currently on any anti-acid agent Prior surgical anti-reflux procedure, including Nissen, Belsey, or Toupet Barrett s esophagus Liver transplantation Pregnancy Allergy or adverse reaction to PPI Intervention PPI group: pantoprazole 40 mg IV x 1 day after banding, then 40 mg orally for 9 days Control group: NS IV bolus following banding, then placebo tablet for 9 days All patients were on a β-blocker if tolerated Endpoints Primary endpoint: Size of esophageal ulcers at day follow-up endoscopy after original banding Baseline Characteristics Results Secondary Endpoints: Occurrence of bleeding complications post-banding Number of esophageal ulcers (adjusted for number of bands placed) Dysphagia and chest pain ratings at follow-up endoscopy after banding Assess safety for second banding procedure, if indicated Global SF-36 score The average age of participants was 50 years. Control (n=20) PPI (n=22) p-value Sex, male, n (%) 14 (64) 10 (45) NS Child Pugh Score A/B/C, n 9/10/3 10/8/4 NS β-blocker at entry, n (%) 12 (55) 15 (68) NS Variceal Grade 1/2/3/4 0/14/8/0 0/16/6/0 NS A total of 44 patients were enrolled and 42 completed the study Control(n=20) PPI (n=22) p-value Bands placed, mean (range) 2.8 (1-5) 3.2 (1-6) - # ulcers at day 10, mean (SE) 2.25 (±0.31) 2.18 (±0.20) NS Ulcer size (mm 2 ) at day 10, mean (SE) 82 (±22) 37 (±9) 0.01 Child-Pugh A/B, mean Child-Pugh C, mean SF-36 between control and PPI: NS A. Whitaker 13 of 20

14 Safety: Bleeding events: control 2/20; PPI 0/22; NS o Post-banding ulcer bleeding Dysphagia: control 1/20 (5%); PPI 3/22 (14%) Chest pain: control 0/20 (0%); PPI 1 /22 (5%) Authors Conclusion Use of PPI reduces the size of the post-banding ulcer by 50% at follow-up endoscopy and should be implemented due to benign profile of intervention Strengths Evaluated use of PPI after elective banding for varices Randomized, placebo controlled trial Limitation/Critique Primary endpoint was a surrogate marker Not powered to detect difference in bleeding events Lower incidence of β-blocker therapy in control group, increasing risk for variceal bleed Take away Showed reduced ulcer size with 10 days of PPI use No evaluation on clinical outcomes of increased bleeding risk with PPI use Unequal use of β-blocker therapy could impact bleeding events observed NS: Not statistically significant; SE: standard error Lo G, Perng D, Chang C, et al. Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitors in the control of acute esophageal variceal bleeding. J Gastroenterol Hepatol. 2013;28(4): Objective Compare use of vasoconstrictors and PPI use in cirrhotic patients after arrest of acute variceal bleeding by banding Design/Method Patient Population Randomized, single-blinded, non-inferiority controlled trial Inclusion: Acute variceal bleeding Cirrhosis Age Emergency banding stopped bleeding Exclusion: Severe systemic illness - sepsis, COPD, uremia Gastric variceal bleeding Failure to control bleed with banding Died within 12 hours of enrollment Banding or scleroptherapy within 1 month of enrollment Child-Pugh s score > 13 Hepatocellular carcinoma Intervention PPI group: pantoprazole or omeprazole 40 mg IV x 5 days, then pantoprazole 40 mg PO x 14 days Vasoconstrictor group: somatostatin CI250 µg/hr or terlipressin 1 mg q 6 hours x 5 days Standard therapy: FFP, fluids and electrolytes replacement, cefazolin 1 g every 6 hours for 5 days, and lactulose as clinically indicated Endpoints Primary endpoints: Failure to control of acute bleeding 1 Secondary endpoint: Very early re-bleeding 2, treatment failure 3, esophageal ulcer bleeding, adverse events, blood requirements, and 42-day mortality and re-bleeding A. Whitaker 14 of 20

15 Definitions Failure to control acute bleeding: at least one of the criteria happened in the first 48 hours: 1)hematemesis after enrollment 2) SBP drop of 20 mmhg ± HR 20 bpm with 2 g hemoglobin drop 3) transfusion of 4 units of blood to keep hematocrit > 27% or hemoglobin > 9 g/dl 4) death Very early re-bleeding: developed one of the above criteria within hours Treatment failure: failure to control acute bleed, very early re-bleeding, or death within 5 days Baseline Characteristics Results Average age was 53 and majority of participants were male Vasoconstrictor (n=60) PPI (n=58) p-value MELD score 12.4 ± ± 4.2 NS Child Pugh Score A/B/C, n 18/32/10 15/24/19 NS Active variceal bleeding NS EV size F1/F2/F3* 5/31/24 5/33/20 NS *See Appendix D for definition A total of 186 screened 118 randomized Vasoconstrictor(n=60) PPI(n=58) p-value Bands placed, mean (range) 3.5 (2-5) 3.2 (3-5) NS Failure to control acute bleeding 1 0 NS Very early re-bleeding 1 1 NS Treatment failure 2 1 NS Total re-bleeding at 6-42 days 5 5 NS Esophageal ulcer 1 0 NS Esophageal varice 3 4 NS Gastric varices 1 1 NS 42-day mortality 4 3 NS Source of very early re-bleeding - esophageal ulcer Observations at follow up endoscopy at 2 weeks Vasoconstrictor (n=21) PPI(n=22) p-value # esophageal ulcers, n (%) 18 (86) 14 (64) NS Esophageal ulcer > 1.5 cm, n (%) 6 (29) 1 (5) <0.04 Vasoconstrictor (n=60) PPI (n=58) p-value Adverse Effect 33 3 <0.001 Chest pain 9 0 <0.01 Abdominal pain 13 0 <0.01 Esophageal ulcer bleeding 2 1 NS A. Whitaker 15 of 20

16 Authors Conclusion Once bleeding is stopped by banding, PPI s were just as effective as vasoconstrictors at maintaining homeostasis and preventing very early rebleeding. PPI s price, adverse effect profile and ability to heal ulcers have advantages over the vasoconstrictors. Strengths Provided a study with direct comparison of vasoconstrictor (current standard of therapy) to PPI therapy Randomized controlled trial Excluded gastric varices which is a confounding variable for use of PPI Limitation/Critique Inappropriate use of statistical analysis o Non-inferiority with no delta or hazard ratio or 95% confidence interval were given for interpretation Somatostatin and terlipressin were used in the vasoconstrictor group. o Not standard of care in US o o Terlipressin has more side effects Somatostatin is less potent than octreotide which could lead to less effectiveness Non-guideline directed SBP prophylaxis increasing risk for SBP and rebleeding Take away No difference in re-bleeding after banding Smaller size in the ulcer around the banded varices Increased adverse effects due to vasoconstrictors of choice, non-standard of care in the US NS: Not statistically significant; CI: Continuous infusion SUMMARY I. PPI Efficacy post-banding A. Decreased ulcer size after banding B. Reduction in bleeding events has not been correlated with PPI use after banding C. Other causes have consistently shown to be risk factors for risk of re-bleeding 1. Emergent banding 2. Child-Pugh score 9 3. MELD Alcoholic cirrhosis II. Safety in cirrhotic patients A. Duration 1. Appears to be safe when used within first 24 hours of an acute bleed with EGD therapy 2. Greater than 90 days: a. Increase risk for severe SBP, CDI, pneumonia, and other complications 3. Intermediate (24 hours to 90 days): no clear evidence for harm B. Prescribing habits 1. PPI continued for at least 2-6 months post hospitalization and after diagnosis of varices A. Whitaker 16 of 20

17 III. Dosing A. Studies have used pantoprazole 40 mg IV once daily for 1-5 days, followed by pantoprazole 40 mg by mouth for 9-14 days RECOMMENDATIONS Figure 4: Recommendation for use of PPI post-banding I. Consider using PPI after variceal bleeds when there is data supported co-morbid indications A. Data supported indications: 1. GERD 2. Erosive esophagitis 3. Gastric ulcers 4. Duodenal ulcers 5. Hypersecretory conditions II. Areas for further studies A. Portal hypertension gastropathy B. Gastric varices A. Whitaker 17 of 20

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19 22. DRUGDEX System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: Accessed October 23, Lodato F, Azzaroli F, Di Girolamo M, et al. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol. 2008; 14 (19): Shin JM and Kim N. Pharmacokinetic and pharmacodynamics of the proton pump inhibitors. J Neuroastroenterol Motil. 2013;19(1): Gralnek IM, Barkun AN, and Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J Med Aug 28;359(9): Barkun AN, Cockeram AW, Plourde V, Fedorak RN. Review article: acid suppression in non-variceal acute upper gastrointestinal bleeding. Aliment Pharmacol Ther 1999;13: Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA Oct 27;292(16): McDonald EG, Milligan J, Frenette C, and Lee TC. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection. JAMA Intern Med May;175(5): Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296: Laine and Jensen. Management of patients with ulcer bleeding. Am J Gastroenterol 2012;107: Goel GA, Deshpande A, Lopez R, Hall GS, Van Duin D, Carey WD. Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol. 2012;10: Chavez-Tapia NC, Tellez-Avila FI, Garcia-Leiva J, Valdovinos MA. Use and overuse of proton pump inhibitors in cirrhotic patients. Med Sci Monit. 2008;14:CR Kalaitzakis E and Bjomsson E. Inadequate use of proton-pump inhibitors in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2008; 20: Bajaj J, Zadvornova Y, Heuman D, et al. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol. 2009;104: Siple JF, Morey JM, Gutman TE, et al. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. 2012; 46(10): Trikudanathan G, Israel J, Cappa J, O Sullivan DM. Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients a systematic review and meta-analysis. Int J Clin Pract. 2011;66: Wiest R, Krag A, and Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut Feb;61(2): Bajaj JS. Anathakrishnan AN. Hafeezullah M, et al. Clostridium difficile is associated withpoor outcomes in patients with cirrhosis: a national and teriary center perspective. Am J Gastroenterol 2010;105: Lo EAG, Wilby KJ, and Ensom MHH. Use of proton pump inhibitors in the management of gastroesophageal varices: a systematic review. Ann Pharmacother. 2015; 49(2): Alaniz C, Mohammad RA, Welage LS. Pharmacotherapy. 2009; 29 (3): Shaheen NJ, Stuart E, Schmitz SM, et al. Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005;41: Lo G, Perng D, Chang C, et al. Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitors in the control of acute esophageal variceal bleeding. J Gastroenterol Hepatol. 2013;28(4): A. Whitaker 19 of 20

20 Appendix A: Child Pugh Classification for Cirrhosis Severity 4 Points Encephalopathy None Grade 1-2 Grade 3-4 (precipitant-induced) (Chronic) Ascites None Mild/Moderate Tense (diuretic-responsive) (diuretic-refractory) Bilirubin (mg/dl) <2 2-3 >3 Albumin (g/dl) > <2.8 Prolong PT or INR <4 or < or > Interpretation a. Child-Pugh score A: 5-6 points b. Child-Pugh score B: 7-9 points c. Child-Pugh score C: points Appendix B: Portal Hypertension HVPG measurements 4 HVPG measurements Interpretation 3-5 mmhg Normal > mmhg Predictive for esophageal varices >20 mmhg In the presence of bleeding; predictive of early re-bleeding Appendix C Variceal Size classification 4 Size Semi-quantitative morphological Assessment Quantitative size Small minimally elevated veins above the esophageal mucosal 5 mm in diameter surface Medium tortuous veins occupying less than one-third of the esophageal lumen > 5 mm in diameter Large occupying more than one-third of the esophageal lumen Appendix D Variceal Grading on shape and size Grade Semi-quantitative morphological Assessment F0 No esophageal varices F1 Small straight esophageal varices F2 Slightly enlarged tortuous esophageal varices < 1/3 size of the lumen F3 Large coil-shaped EV that occupied > 1/3 of the esophageal lumen A. Whitaker 20 of 20